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Astrocytic chloride is brain state dependent and modulates inhibitory neurotransmission in mice.

ABSTRACT: Information transfer within neuronal circuits depends on the balance and recurrent activity of excitatory and inhibitory neurotransmission. Chloride (Cl^-) is the major central nervous system (CNS) anion mediating inhibitory neurotransmission. Astrocytes are key homoeostatic glial cells populating the CNS, although the role of these cells in regulating excitatory-inhibitory balance remains unexplored. Here we show that astrocytes act as a dynamic Cl^- reservoir regulating Cl^- homoeostasis in the CNS. We found that intracellular chloride concentration ([Cl^-]_i) in astrocytes is high and stable during sleep. In awake mice astrocytic [Cl^-]_i is lower and exhibits large fluctuation in response to both sensory input and motor activity. Optogenetic manipulation of astrocytic [Cl^-]_i directly modulates neuronal activity during locomotion or whisker stimulation. Astrocytes thus serve as a dynamic source of extracellular Cl^- available for GABAergic transmission in awake mice, which represents a mechanism for modulation of the inhibitory tone during sustained neuronal activity.

SUBMITTER: Untiet V

PROVIDER: S-EPMC10073105 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Astrocytic chloride is brain state dependent and modulates inhibitory neurotransmission in mice.

Untiet Verena V Beinlich Felix R M FRM Kusk Peter P Kang Ning N Ladrón-de-Guevara Antonio A Song Wei W Kjaerby Celia C Andersen Mie M Hauglund Natalie N Bojarowska Zuzanna Z Sigurdsson Björn B Deng Saiyue S Hirase Hajime H Petersen Nicolas C NC Verkhratsky Alexei A Nedergaard Maiken M

Nature communications 20230404 1

Information transfer within neuronal circuits depends on the balance and recurrent activity of excitatory and inhibitory neurotransmission. Chloride (Cl<sup>-</sup>) is the major central nervous system (CNS) anion mediating inhibitory neurotransmission. Astrocytes are key homoeostatic glial cells populating the CNS, although the role of these cells in regulating excitatory-inhibitory balance remains unexplored. Here we show that astrocytes act as a dynamic Cl<sup>-</sup> reservoir regulating Cl< ...[more]

PMID: 37015909

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Project description:BackgroundComplex changes in the brain microenvironment following traumatic brain injury (TBI) can cause neurological impairments for which there are few efficacious therapeutic interventions. The reactivity of astrocytes is one of the keys to microenvironmental changes, such as neuroinflammation, but its role and the molecular mechanisms that underpin it remain unclear.MethodsMale C57BL/6J mice were subjected to the controlled cortical impact (CCI) to develop a TBI model. The specific ligand of AXL receptor tyrosine kinase (AXL), recombinant mouse growth arrest-specific 6 (rmGas6) was intracerebroventricularly administered, and selective AXL antagonist R428 was intraperitoneally applied at 30 min post-modeling separately. Post-TBI assessments included neurobehavioral assessments, transmission electron microscopy, immunohistochemistry, and western blotting. Real-time polymerase chain reaction (RT-PCR), siRNA transfection, and flow cytometry were performed for mechanism assessments in primary cultured astrocytes.ResultsAXL is upregulated mainly in astrocytes after TBI and promotes astrocytes switching to a phenotype that exhibits the capability of ingesting degenerated neurons or debris. As a result, this astrocytic transformation promotes the limitation of neuroinflammation and recovery of neurological dysfunction. Pharmacological inhibition of AXL in astrocytes significantly decreased astrocytic phagocytosis both in vivo and in primary astrocyte cultures, in contrast to the effect of treatment with the rmGas6. AXL activates the signal transducer and activator of the transcription 1 (STAT1) pathway thereby further upregulating ATP-binding cassette transporter 1 (ABCA1). Moreover, the supernatant from GAS6-depleted BV2 cells induced limited enhancement of astrocytic phagocytosis in vitro.ConclusionOur work establishes the role of AXL in the transformation of astrocytes to a phagocytic phenotype via the AXL/STAT1/ABCA1 pathway which contributes to the separation of healthy brain tissue from injury-induced cell debris, further ameliorating neuroinflammation and neurological impairments after TBI. Collectively, our findings provide a potential therapeutic target for TBI.

Dataset Information

Astrocytic chloride is brain state dependent and modulates inhibitory neurotransmission in mice.

Publications

Astrocytic chloride is brain state dependent and modulates inhibitory neurotransmission in mice.

Similar Datasets

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